Tumor growth requires high energy and nutrient supplies. As a result, cancer cells usually undergo various types of metabolic stress. Overcoming metabolic stress is a critical step in cancer development. However, how cancer cells engage strategies of metabolic adaptation to survive and grow under metabolic stress is not well understood. Our long-term goal is to study key signaling pathways in metabolic stress response in the context of cancer development, so as to enable the medical community to rationally target such pathways in the treatment of human cancers. The objective of this application is to study the roles of FoxO transcription factors (FoxOs) in energy stress response and tumor suppression in renal cell carcinoma (RCC). Our extensive preliminary data support the central hypothesis of our proposal that FoxO-BNIP3 axis plays a dual role in inhibiting both cell growth (cell size increase) and cell survival in response to energy stress, and loss of FoxOs or BNIP3 is one important strategy renal cancer cells adapt to energy stress during tumor development. The rationale for the proposed research is that studying the roles of FoxO signaling in energy stress response and renal tumor suppression will advance our understanding of how renal cancer cells bypass energy stress to survive and grow, and will provide important insights on the development of novel therapeutic strategies or prognostic markers targeting metabolic stress in renal cancer treatment. To test our hypothesis, we will pursue the following specific aims: Specific Aim 1. To determine the regulation and mechanisms of FoxO signaling in energy stress response in renal cancer cells. Specific Aim 2. To determine the roles of FoxOs and BNIP3 in mTORC1 inhibition and renal tumor suppression in vivo. With respect to expected outcomes, our proposed studies will identify novel mechanisms of energy stress pathways, clarify the tumor suppression function of FoxO and BNIP3 in renal cancer, and provide important insights on the use of FoxO/BNIP3 expression in prognostic stratification of renal cancer patients. Our proposal is highly innovative, because it focuses on a previously unexplored pathway that fills in the current gap to link energy stress to renal tumor development. Our proposed studies will have significant impact on both understanding the fundamental mechanisms of energy stress signaling and manipulating energy stress pathways clinically in the stratification and treatment of human cancer patients.